Open AccessA Cyclic Phosphoramidate Prodrug of 2′-Deoxy-2′-Fluoro-2′- C -Methylguanosine for the Treatment of Dengue Virus Infection
Author(s) -
Ratna Karuna,
Fumiaki Yokokawa,
Keshi Wang,
Jin Zhang,
Haoying Xu,
Gang Wang,
Mei Ding,
Wai Ling Chan,
Nahdiyah Abdul Ghafar,
Andrea Leonardi,
Cheah Chen Seh,
Peck Gee Seah,
Wei Liu,
Rao P S Srinivasa,
Siew Pheng Lim,
Suresh B. Lakshminarayana,
Ellena Growcott,
Sreehari Babu,
Martijn Fenaux,
Weidong Zhong,
Feng Gu,
Pei–Yong Shi,
Francesca Blasco,
Yen-Liang Chen
Publication year - 2020
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.00654-20
Subject(s) - prodrug , phosphoramidate , dengue virus , hepatitis c virus , virology , virus , peripheral blood mononuclear cell , nucleoside , biology , chemistry , pharmacology , biochemistry , in vitro
Monophosphate prodrug analogs of 2'-deoxy-2'-fluoro-2'- C -methylguanosine have been reported as potent inhibitors of hepatitis C virus (HCV) RNA-dependent RNA polymerase. These prodrugs also display potent anti-dengue virus activities in cellular assays although their prodrug moieties were designed to produce high levels of triphosphate in the liver. Since peripheral blood mononuclear cells (PBMCs) are among the major targets of dengue virus, different prodrug moieties were designed to effectively deliver 2'-deoxy-2'-fluoro-2'- C -methylguanosine monophosphate prodrugs and their corresponding triphosphates into PBMCs after oral administration. We identified a cyclic phosphoramidate, prodrug 17, demonstrating well-balanced anti-dengue virus cellular activity and in vitro stability profiles. We further determined the PBMC concentration of active triphosphate needed to inhibit virus replication by 50% (TP 50 ). Compound 17 was assessed in an AG129 mouse model and demonstrated 1.6- and 2.2-log viremia reductions at 100 and 300 mg/kg twice a day (BID), respectively. At 100 mg/kg BID, the terminal triphosphate concentration in PBMCs exceeded the TP 50 value, demonstrating TP 50 as the target exposure for efficacy. In dogs, oral administration of compound 17 resulted in high PBMC triphosphate levels, exceeding the TP 50 at 10 mg/kg. Unfortunately, 2-week dog toxicity studies at 30, 100, and 300 mg/kg/day showed that "no observed adverse effect level" (NOAEL) could not be achieved due to pulmonary inflammation and hemorrhage. The preclinical safety results suspended further development of compound 17. Nevertheless, present work has proven the concept that an efficacious monophosphate nucleoside prodrug could be developed for the potential treatment of dengue virus infection.